Many aspects of behavior and physiology, such as sleeping and wakefulness, blood pressure, and body temperature exhibit daily oscillations known as circadian rhythms. Disturbances in these circadian rhythms are responsible for the debilitating effects of jet lag, shift work and the sleep disorders seen in patients suffering from Alzheimer's disease. Circadian rhythms are driven by an intrinsic biological clock found in organisms ranging from plants to humans. In mammals, this biological clock is housed deep within the brain in two small clusters of cells called the suprachiasmatic nuclei (SCN). These intrinsic circadian rhythms are synchronized to the daily environmental cycle of day and night by the process of photoentrainment, which uses light information to reset the biological clock. In mammals, the neuronal signal for photoentrainment arises from a small subset of retinal ganglion cells (RGCs) that send a direct projection to the SCN. Surprisingly, the retinal signals that give rise to vision may be quite different from those responsible for circadian entrainment. Although retinal input is required for photoentrainment, traditional photoreceptors are not required. The solution to this apparent paradox may lie in the recent discovery that RGCs that project to the SCN express a novel photopigment, melanopsin, and can generate an intrinsic light response in the absence of photoreceptor-driven synaptic input. To date, little is known about the physiology of the RGCs that generate the retinal output to the circadian system. In this grant, we propose to use a multidisciplinary approach to study how these cells generate the retinal signals that produce photoentrainment. Specifically, we will determine 1) the signaling properties of melanopsin, the photopigment of the circadian system; 2) what intracellular signaling pathway generates the intrinsic response to light; and 3) the ion channel that mediates the intrinsic light response. This research will provide a foundation for improved treatment of circadian disorders that are often associated with neurological disorders, and are responsible for the debilitating effects of jet lag and shift work.